The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human
cancers including ovarian cancer, where they are associated with disease
progression at the levels of tumor cell proliferation, invasion, and
angiogenesis. Here we used an immunocompetent mouse model of intraperitoneal
papillary epithelial ovarian cancer to demonstrate that modulation of the
CXCL12/CXCR4 axis in ovarian cancer has multimodal effects on tumor pathogenesis
associated with induction of antitumor immunity. siRNA-mediated knockdown of
CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell
proliferation in vitro and tumor growth in vivo. Similarly, treatment of
BR5-1-derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in
increased tumor apoptosis and necrosis, reduction in intraperitoneal
dissemination, and selective reduction of intratumoral FoxP3+ regulatory T-cells
(T-regs). Compared to controls, CXCR4 blockade greatly increased T cell-mediated
antitumor immune responses, conferring a significant survival advantage to
AMD3100-treated mice. In addition, the selective effect of CXCR4 antagonism on
intratumoral T regulatory cells was associated with both higher CXCR4 expression
and increased chemotactic responses to CXCL12, a finding that was also confirmed
in a melanoma model. Together, our findings reinforce the concept of a critical
role for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer a
definitive preclinical validation of CXCR4 as a therapeutic target in this
disease.
While agents that inhibit specific oncogenic kinases have been successful in a subset of cancers, there are currently few treatment options for malignancies that lack a targetable oncogenic driver. Nevertheless, during tumor evolution cancers engage a variety of protective pathways, which may provide alternative actionable dependencies. Here we identify a promising combination therapy that kills NF1-mutant tumors by triggering catastrophic oxidative stress. Specifically, we show that mTOR and HDAC inhibitors kill aggressive nervous system malignancies and shrink tumors in vivo by converging on the TXNIP/thioredoxin anti-oxidant pathway, through cooperative effects on chromatin and transcription. Accordingly, TXNIP triggers cell death by inhibiting thioredoxin and activating Apoptosis Signal-regulating Kinase 1 (ASK1). Moreover, this drug combination also kills NF1-mutant and KRAS-mutant non-small cell lung cancers. Together these studies identify a promising therapeutic combination for several currently untreatable malignancies, and reveal a protective nodal point of convergence between these important epigenetic and oncogenic enzymes.
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